Thrombin is an important serine protease that is involved in hemostasis and thrombosis. One of the key actions of thrombin is cellular modulation via receptor activation. A functional human thrombin receptor (PAR-1), cloned by Coughlin in 1991 (T.-K. Vu, Cell 1991, 64, 1057), is a member of the G-protein-coupled receptor (GPCR) superfamily. Thrombin receptor activation occurs by N-terminal recognition and proteolytic cleavage to reveal a truncated N-terminus. This new receptor sequence can trigger activation and signal transduction leading to platelet aggregation. Since 1991, three other protease-activated receptors with extensive homology to the thrombin receptor, “PAR-2” (S. Nystedt, Proc. Natl. Acad. Sci. USA 1994, 91, 9208), “PAR-3” (H. Ishihara, Nature 1997, 386, 502), and “PAR-4” (W.-F. Xu, Proc. Natl. Acad. Sci. USA 1998, 95, 6642), have been identified. Thrombin receptor (PAR-1) specific antibody-induced blockade of the platelet thrombin receptor has shown efficacy against arterial thrombosis in vivo (J. J. Cook Circulation 1995, 91, 2961). Hence, antagonists of the thrombin receptor (PAR-1) are useful to block these protease-activated receptors and, as such, would be useful for treating platelet-mediated thrombotic disorders, such as myocardial infarction, stroke, restenosis, atherosclerosis, and ischemic conditions.
The thrombin receptor (PAR-1) has also been identified on other cell types, such as endothelial, fibroblast, renal, osteosarcoma, smooth muscle, myocytes, tumor, and neuronal/glial. Thrombin activation of endothelial cells up-regulates P-selectin to induce polymorphonuclear leukocyte adhesion, an inflammatory response of the vessel wall (Y. Sugama, J. Cell Biol. 1992, 119, 935). In fibroblasts, thrombin receptor (PAR-1) activation induces proliferation and transmission of mitogenic signals (D. T. Hung, J. Cell Biol. 1992, 116, 827). Thrombin has been implicated in osteoblast proliferation through its activation of osteoblast cells (D. N. Tatakis, Biochem. Biophys. Res. Commun. 1991, 174, 181). Thrombin has been implicated in the regulation and retraction of neurons (K. Jalink, J. Cell. Biol. 1992, 118, 411). In this context, the antagonist compounds of this invention may also be useful for treating inflammation, osteoporosis, angiogenesis and related disorders, cancer, neurodegenerative disorders and/or glomerulonephritis.